Both low and high body mass indexes (BMI) are associated with the increased risk of coronary heart disease (CHD) and death. The molecular mechanism that underlies the deadly link, however, remains the subject of considerable speculation. Our long-term objective is to understand the role of the genetic program of tissue remodeling in regulating the association between adiposity and CHD. MMP14 encodes a membrane-type matrix metalloproteinase (MMP) that plays the major role in the physiological remodeling of extracellular matrix (ECM). MMP14 gene reduction (haploinsufficiency) renders mice resistant to high-fat diet induced ECM remodeling and gene expression. Unexpectedly, however, these leaner mice display inflammatory adipose tissue profile and aggravated atherosclerosis in ApoE knockout background. Our central hypothesis is that, under atherogenic nutritional challenge, enhanced MMP14 gene expression is required to maintain anti-fibrotic and anti-inflammatory states of adipose tissues and vascular walls. To test this central hypothesis, we propose the following two specific aims in this R21 mechanism. #1: Determine the role of MMP14 expressed by adipocytes in regulating systemic inflammation and atherosclerosis, and #2: Determine the role of MMP14 expressed by vascular smooth muscle cells in regulating vascular wall remodeling, inflammation and atherosclerosis. As approach, we utilize cell type-selective MMP14 gene targeting in mice to assess the effect on vascular wall tissue damage, inflammation and gene regulation. Through these studies, we are able to determine the role of MMP14 expressed by adipocytes and vascular smooth muscle cells in regulating atherogenesis. Expected outcomes will advance our understanding of the molecular mechanism underlying the disease link between obesity and CHD. PUBLIC HEALTH RELEVANCE: Statement Obesity increases the risk of coronary heart disease (CHD). This research aims to determine the role of enzyme-mediated tissue remodeling in regulating the link between fat mass and atherosclerosis. Expected outcomes will help us develop a new approach to obesity and CHD.